A population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of a novel MDR modulator, zosuquidar trihydrochloride (LY335979)Citation formats

  • External authors:
  • Sophie Callies
  • Dinesh P. De Alwis
  • James G. Wright
  • Alan Sandler
  • Michael Burgess

Standard

A population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of a novel MDR modulator, zosuquidar trihydrochloride (LY335979). / Callies, Sophie; De Alwis, Dinesh P.; Wright, James G.; Sandler, Alan; Burgess, Michael; Aarons, Leon.

In: Cancer Chemotherapy and Pharmacology, Vol. 51, No. 2, 01.02.2003, p. 107-118.

Research output: Contribution to journalArticle

Harvard

Callies, S, De Alwis, DP, Wright, JG, Sandler, A, Burgess, M & Aarons, L 2003, 'A population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of a novel MDR modulator, zosuquidar trihydrochloride (LY335979)', Cancer Chemotherapy and Pharmacology, vol. 51, no. 2, pp. 107-118.

APA

Callies, S., De Alwis, D. P., Wright, J. G., Sandler, A., Burgess, M., & Aarons, L. (2003). A population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of a novel MDR modulator, zosuquidar trihydrochloride (LY335979). Cancer Chemotherapy and Pharmacology, 51(2), 107-118.

Vancouver

Callies S, De Alwis DP, Wright JG, Sandler A, Burgess M, Aarons L. A population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of a novel MDR modulator, zosuquidar trihydrochloride (LY335979). Cancer Chemotherapy and Pharmacology. 2003 Feb 1;51(2):107-118.

Author

Callies, Sophie ; De Alwis, Dinesh P. ; Wright, James G. ; Sandler, Alan ; Burgess, Michael ; Aarons, Leon. / A population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of a novel MDR modulator, zosuquidar trihydrochloride (LY335979). In: Cancer Chemotherapy and Pharmacology. 2003 ; Vol. 51, No. 2. pp. 107-118.

Bibtex

@article{dcc1bdba8ac84d338d710782ca1c3ba9,
title = "A population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of a novel MDR modulator, zosuquidar trihydrochloride (LY335979)",
abstract = "Purpose: To develop a population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of zosuquidar.3HCl, a potent P-glycoprotein inhibitor. Methods: The population approach was used (implemented with NONMEM) to analyse doxorubicin-doxorubicinol pharmacokinetic data from 40 patients who had received zosuquidar.3HCl and doxorubicin intravenously (separately in cycle 1 and concomitantly in cycle 2 over 48 h and 0.5 h, respectively). Results: A five-compartment pharmacokinetic model (including three compartments for doxorubicin pharmacokinetics with two pathways for doxorubicinol formation) best described the doxorubicin-doxorubicinol pharmacokinetics in the presence of zosuquidar.3HCl. Doxorubicin clearance (CL), peripheral volume of distribution (V2) and doxorubicinol apparent clearance (CLm/fm) and apparent volume of distribution (Vm/fm) were 62.3 1/h, 2360 1, 143 1/h and 3150 1, respectively, in the absence or presence of low doses of zosuquidar.3HC1 (<500 mg). In the presence of high doses of zosuquidar.3HCl (≥500 mg), these values decreased by 25{\%}, 26{\%}, 48{\%} and 73{\%}, respectively, and doxorubicinol pharmacokinetics were characterized by a delayed tmax (24 h versus 4 h), which led to the inclusion of the parallel pathways. A decrease in the objective function (P <0.005) was observed when the impact of zosuquidar.3HCl was accounted for. Conclusions: This integrated parent-metabolite population pharmacokinetic model accurately characterized the increase in doxorubicin and doxorubicinol exposure (1.33- and 2-fold, respectively) in the presence of zosuquidar.3HCl (≥500 mg) and provided insights into the pharmacokinetic interaction, which may be useful in designing future clinical trials.",
keywords = "Doxorubicin, Doxorubicinol, LY335979, NONMEM, Pharmacokinetics",
author = "Sophie Callies and {De Alwis}, {Dinesh P.} and Wright, {James G.} and Alan Sandler and Michael Burgess and Leon Aarons",
year = "2003",
month = "2",
day = "1",
language = "English",
volume = "51",
pages = "107--118",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Nature",
number = "2",

}

RIS

TY - JOUR

T1 - A population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of a novel MDR modulator, zosuquidar trihydrochloride (LY335979)

AU - Callies, Sophie

AU - De Alwis, Dinesh P.

AU - Wright, James G.

AU - Sandler, Alan

AU - Burgess, Michael

AU - Aarons, Leon

PY - 2003/2/1

Y1 - 2003/2/1

N2 - Purpose: To develop a population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of zosuquidar.3HCl, a potent P-glycoprotein inhibitor. Methods: The population approach was used (implemented with NONMEM) to analyse doxorubicin-doxorubicinol pharmacokinetic data from 40 patients who had received zosuquidar.3HCl and doxorubicin intravenously (separately in cycle 1 and concomitantly in cycle 2 over 48 h and 0.5 h, respectively). Results: A five-compartment pharmacokinetic model (including three compartments for doxorubicin pharmacokinetics with two pathways for doxorubicinol formation) best described the doxorubicin-doxorubicinol pharmacokinetics in the presence of zosuquidar.3HCl. Doxorubicin clearance (CL), peripheral volume of distribution (V2) and doxorubicinol apparent clearance (CLm/fm) and apparent volume of distribution (Vm/fm) were 62.3 1/h, 2360 1, 143 1/h and 3150 1, respectively, in the absence or presence of low doses of zosuquidar.3HC1 (<500 mg). In the presence of high doses of zosuquidar.3HCl (≥500 mg), these values decreased by 25%, 26%, 48% and 73%, respectively, and doxorubicinol pharmacokinetics were characterized by a delayed tmax (24 h versus 4 h), which led to the inclusion of the parallel pathways. A decrease in the objective function (P <0.005) was observed when the impact of zosuquidar.3HCl was accounted for. Conclusions: This integrated parent-metabolite population pharmacokinetic model accurately characterized the increase in doxorubicin and doxorubicinol exposure (1.33- and 2-fold, respectively) in the presence of zosuquidar.3HCl (≥500 mg) and provided insights into the pharmacokinetic interaction, which may be useful in designing future clinical trials.

AB - Purpose: To develop a population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of zosuquidar.3HCl, a potent P-glycoprotein inhibitor. Methods: The population approach was used (implemented with NONMEM) to analyse doxorubicin-doxorubicinol pharmacokinetic data from 40 patients who had received zosuquidar.3HCl and doxorubicin intravenously (separately in cycle 1 and concomitantly in cycle 2 over 48 h and 0.5 h, respectively). Results: A five-compartment pharmacokinetic model (including three compartments for doxorubicin pharmacokinetics with two pathways for doxorubicinol formation) best described the doxorubicin-doxorubicinol pharmacokinetics in the presence of zosuquidar.3HCl. Doxorubicin clearance (CL), peripheral volume of distribution (V2) and doxorubicinol apparent clearance (CLm/fm) and apparent volume of distribution (Vm/fm) were 62.3 1/h, 2360 1, 143 1/h and 3150 1, respectively, in the absence or presence of low doses of zosuquidar.3HC1 (<500 mg). In the presence of high doses of zosuquidar.3HCl (≥500 mg), these values decreased by 25%, 26%, 48% and 73%, respectively, and doxorubicinol pharmacokinetics were characterized by a delayed tmax (24 h versus 4 h), which led to the inclusion of the parallel pathways. A decrease in the objective function (P <0.005) was observed when the impact of zosuquidar.3HCl was accounted for. Conclusions: This integrated parent-metabolite population pharmacokinetic model accurately characterized the increase in doxorubicin and doxorubicinol exposure (1.33- and 2-fold, respectively) in the presence of zosuquidar.3HCl (≥500 mg) and provided insights into the pharmacokinetic interaction, which may be useful in designing future clinical trials.

KW - Doxorubicin

KW - Doxorubicinol

KW - LY335979

KW - NONMEM

KW - Pharmacokinetics

M3 - Article

VL - 51

SP - 107

EP - 118

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 2

ER -